Dose Of Glycerol Research Articles

1595 KINETICS AND ADVERSE EFFECTS OF IV GLYCEROL IN REYE'S SYNDROME

In severe cases of Reye's Syndrome, elevated intracranial pressure (ICP) is associated with poor prognosis. Little is known about the pharmacology of high dose IV glycerol as used in Reye's Syndrome. Glycerol pharmacokinetics and adverse effects were studied in nine patients (age 9-20 yrs.) with Reye's Syndrome. Glycerol was administered by continuous infusion over 2 hours with half the dose given over the first 0.5 hour and the remainder over the next 1.5 hour. The dose was adjusted to keep ICP ≤ 15 mm Hg. At steadystate, serial blood samples were collected during glycerol infusion and analyzed by an enzymatic assay specific for glycerol At 0.75-1.75 g/kg/2 hr glycerol doses, the serum levels ranged from 1.48-5.83 mg/ml. Total body clearance ranged from 1.99-5.1 ml/kg/min. Glycerol clearance was not related to SCOT, SGPT, and serum ammonia levels. Glycerol provided effective control of intracranial pressure in all patients. Temporary elevation of serum creatinine and BUN, and presence of hemolysis in two patients was thought to be related to glycerol. Our data demonstrate that a large intersubject variability in glycerol kinetics may account for varying glycerol dosage requirement to control ICP in patients with Reye's Syndrome.

Effects of a single therapeutic dose of glycerol on cerebral metabolism in the brains of young mice: possible increase in brain glucose transport and glucose utilization.

Abstract: This is a study of the effects of a single “therapeutic” dose of glycerol [2 g(22 mmol)/kg i.p.] on brain carbohydrate and energy metabolism in normal nursing weanling mice. Findings were correlated with brain water and electrolyte content and with metabolite changes in plasma, red blood cells, and liver.Plasma glycerol levels peaked at 21 mM 7.5 min after injection and returned to the control value, 0.16 mM, by 2 h. Plasma Na+ concentration decreased and plasma protein increased for as long as 2 h after injection. Although red blood cells were freely permeable to glycerol, there was no evidence for glycerol metabolism in these cells. Glycerol levels in liver paralleled those in plasma. Glycerol injection increased liver glucose concentration 23% and doubled hepatic glycerol‐1‐phosphate levels. Liver ATP levels were reduced 24% after glycerol injection.Brain water concentration was significantly reduced from 7.5 min to 30 min after glycerol injection; brain Na+ and K+ levels were unchanged. There was no evidence for glycerol entry into brain (the amount detected in brain tissue could be explained by the glycerol content in the blood of the brain). While plasma glucose increased 33%, brain glucose increased 87%. Concomitantly there were statistically significant increases in fructose‐1,6‐diphosphate, lactate, α‐ketoglutarate, and malate levels.The disproportionately high brain glucose value suggests increased transport of glucose from the blood to the brain. Increases in fructose‐1,6‐diphosphate, lactate, α‐ketoglutarate, and malate are compatible with an increased metabolic flux in the glycolytic pathway and Krebs citric acid cycle. As has been previously shown for urea and/or mannitol, these changes may result from the effects of the hyperosmolar glycerol solution on the blood‐brain barrier and on cerebral glucose utilization.The sustained lowering of plasma Na+ concentration after a single “therapeutic” glycerol injection suggests a need for monitoring plasma Na+ levels in the clinical situation. Possible lowering of hepatic ATP levels by the use of glycerol in humans is another concern.

The utilisation of glycerol by sheep

Increased but steady concentrations of glycerol and glucose in carotid, jugular and portal plasma of sheep were obtained between 2.5 and 3.5 h after the second of two oral doses of glycerol (2 and a ml/kg body weight with a 6 h interval between) and the concentration of glycerol in portal plasma was greater than in the other vessels. During the last hour of a 3.5 h continuous infusion of [14C]glycerol and [3H]glucose, ie, between 2.5 and 3.5 h after the second dose of glycerol, specific radioactivity(SRA) of glycerol and of [14C] an [3H] glucose were measured in plasma obtained from the three previously mentioned sites in dosed and undosed sheep. Although in dosed sheep the SRA of glycerol in portal plasma was lower than that in jugular plasma, the difference was such that the SRA in jugular plasma could be used to calculate entry rates and the rate of production of glucose from glycerol. Mean (+/- SE) glycerol entry rate in four fed sheep increased from 9.2 +/- 1.2 to 62.7 +/- 0.9 mg C/min after a divided oral dose of glycerol. Mean glucose entry rate increased from 29.0 +/0 3.4 to 58.3 +/- 7.6 mg C/min. The amount of glucose which was derived from glycerol increased from 5.4 +/- 1.6 to 35.5 +/- 3.7 mg C/min. This increase accounted for the increase in total glucose entry.

The involvement of phosphatidate phosphohydrolase and phospholipase A activities in the control of hepatic glycerolipid synthesis. Effects of acute feeding with glucose, fructose, sorbitol, glycerol and ethanol

Rats were fed by stomach tube with a single dose of glucose, sorbitol, fructose, glycerol or ethanol of equivalent energy contents or with 0.15 M-NaCl. They were killed 6 h later and the relative rates of phosphatidate deacylation and dephosphorylation measured in the microsomal and supernatant fractions of the livers. Treatment with sorbitol, fructose, glycerol and ethanol increased phosphohydrolase activities in the microsomal and supernatant fractions. The only significant change in deacylase activity was an increase in the microsomal fraction produced by ethanol. It is proposed that hepatic triacylglycerol synthesis is partly controlled by the balance between phosphatidate phosphohydrolase and phospholipase A-type activities.

The effect of oral glycerol on intraventricular pressure in man.

Oral glycerol was administered to eight patients with meningeal carcinomatosis or acute leukemia in whom ventricular catheters and Ommaya reservoirs had been implanted for the purpose of intrathecal chemotherapy or chemoprophylaxis. Intraventricular pressure was monitored continuously via the Ommaya reservoirs before and after single doses of 0.5, 1.0 or l.5 gm per kilogram of body weight. The interrelationship between initial pressure, change in pressure, serum osmolarity, and duration of action was investigated, and the ratio of CSF-to-plasma osmolarity was determined 4 to 5 hours after glycerol administration. The effects of chronic 6-hourly and 4-hourly 1 gm per kilogram glycerol doses were studied in a patient with meningeal carcinomatosis and increased intracranial pressure. Our data suggest that as a cerebral dehydrating agent oral glycerol is most effective in patients with markedly increased intracranial pressure. A single 1 gm per kilogram dose is adequate to lower raised intraventricular pressure acutely, but its effect is short-lived. Continuous oral administration must be carefully monitored to avoid the establishment or a reverse osmotic gradient, secondarily increased intracranial pressure, and clinical deterioration.

Gluconeogenesis in Infancy and Childhood: I. A Method for the Study of the in vivo Gluconeogenesis from Alanine and Glycerol

The in vivo gluconeogenesis from alanine and glycerol in infants and children was studied by an isotope method, using 14C-labeled substrates with subsequent separation of the radioactive compounds by thin-layer chromatography. Seven patients, aged 2 months to 2 years 11 months, with normal carbohydrate metabolism were studied. Trace amounts of [14C] alanine were injected intravenously in four fasting patients. The 14C moved quickly from alanine to lactate, with a peak activity in lactate obtained before 5 min. From 10 min on, the label disappeared rapidly from both. An equilibrium was established between alanine and lactate, displaced towards lactate. The peak activity in glucose was reached in 10—20 min, amounting to 10% of the total injected activity. In one patient, who was also studied after a meal, the disappearance rate of alanine was reduced by 50%. Despite this reduction the appearance of label in lactate was increased, whereas the amount of label in glucose was much reduced. [14C]glycerol was injected intravenously in three fasting patients. In one patient, who received only a tracer dose of glycerol, 5 times more 14C appeared in glucose than in the patients studied with [14C]alanine. In two patients receiving a glycerol load together with the [14C]glycerol, the disappearance rate of glycerol was markedly reduced, as was the conversion of carbon to glucose and lactate.

Gluconeogenesis in infancy and childhood. I. A method for the study of the in vivo gluconeogenesis from alanine and glycerol.

The in vivo gluconeogenesis from alanine and glycerol in infants and children was studied by an isotope method, using 14C-labeled substates with subsequent separation of the radioactive compounds by thin-layer chromatography. Seven patients, aged 2 months to 2 years 11 months, with normal carbohydrate metabolism were studied. Trace amounts of [14C]alanine were injected intravenously in four fasting patients. The 14C moved quickly from alanine to lactate, with a peak activity in lactate obtained before 5 min. From 10 min on, the label disappeared rapidly from both. An equilibrium was established between alanine and lactate, displaced towards lactate. The peak activity in glucose was reached in 10-20 min, amounting to 10% of total injected activity. In one patient, who was also studied after a meal, the disappearance rate of alanine was reduced by 50%. Despite this reduction the appearance of label in lactate was increased, whereas the amount of label in glucose was much reduced. [14C]glycerol was injected intravenously in three fasting patients. In one patient, who received only a tracer dose of glycerol, 5 times more 14C appeared in glucose than in the patients studied with [14C]alanine. In two patients receiving a glycerol load together with the [14C]glycerol, the disappearance rate of glycerol was markedly reduced, as was the conversion of carbon to glucose and lactate.

Rebound phenomenon complicating cerebral dehydration with glycerol

A patient with glioblastoma multiforme of the brain was treated with both intravenous and oral glycerol as well as intravenous mannitol in an attempt to reduce increased intracranial pressure. After an initial lowering of the cerebrospinal fluid (CSF) pressure to near normal values during continuous glycerol administration, a secondary rise in CSF pressure above the initial level occurred despite a persistent elevation of plasma osmolality (315 mOsm/kg) and glycerol level (30 mmole/l). Similarly, 4 hours after the administration of a single oral dose of glycerol, CSF pressure increased to levels higher (700 mm H2O) than the original baseline (400 mm H2O).

Active and passive immunization to angiotensin in experimental acute renal failure

A number of studies support, and others fail to support, the concept that the renin-angiotensin system plays a key role in the pathogenesis of acute renal failure. This study, employing active and passive immunization against angiotensin II, was designed to examine the primacy of circulating angiotensin as a mediator of this syndrome. Neither mode of immunization significantly affected the degree of azotemia or the marked reduction of inulin clearance expected in rats subjected to glycerol-induced myohemoglobinuria. Twenty-four hours after challenge, inulin clearance (Cin) in actively immunized rats fell to 3.2% of control and that of unimmunized rats given the same dose of glycerol was 2.5% of control. Although there was some variation among groups of passively immunized rats, Cin of one group being 18% of control, Cin of the other groups was less than 3% of control. The dose and binding capacity of the immune globulin used here were essentially the same as those reported in another study in which immunization was thought to be of prophylactic value in rats subjected to s.c. administered glycerol injections. Technologic differences unrelated to immunization are suggested to have caused the difference in results in the two studies, and it seems doubtful that circulating angiotensin plays a key role in the pathogenesis of myohemoglobinuric acute renal failure in the rat.

Effect of furosemide on antibiotic-induced renal damage in rats.

Cephaloridine is known to be nephrotoxic to man and animals. It has recently been suggested that diuretics may enhance this effect. Experiments in rats were undertaken to explore this relationship further. Rats were given a small dose of glycerol to induce mild, transient renal impairment. Thereafter, they received one of several nephrotoxic antibiotics either alone or in association with the diuretic furosemide. At a standard interval after the administration of the drugs, the animals were sacrificed and their kidneys removed for histologic examination. The resulting data indicate that in the rat with transient renal impairment, the nephrotoxicity of four antibiotics (cephaloridine, cephalothin, colistin, and kanamycin) is enhanced by coincidental administration of furosemide. In the case of cephaloridine, this effect was marked when the concentrations of drug in blood were similar to those attained in humans during routine therapy.

Cerebral dehydration action of glycerol. I. Historical aspects with emphasis on the toxicity and intravenous administration.

Oral glycerol (1 Gm. per kilogram every 6 hours) has a dehydration effect on the central nervous system. Prolonged continuous administration of glycerol does not produce marked alteration of fluid and electrolytes. It is almost totally excluded from the brain, which excludes the problem of rebound overhydration. It has significant nutritional value nad none of the side effects of steroids. The major toxic effects of glycerol (hemolysis, hemoglobinuria, and renal failure) can be prevented and are a function of concentration and route of administration. Glycerol does not hemolyze red blood cells when it is prepared with isotonic saline in concentrations up to 40 per cent. Human intravenous glycerol has been used safely on a number of occasions with plasma levels reaching 10 mmoles per liter to measure turnover rates in adults and infants. The same oral glycerol dose is effective in lowering ocular tension and cerebrospinal fluid pressure. The plasma concentration response curve for normal human eyes has been previously determined. Intraocular pressure begins to fall when plasma glycerol is approximately 10 mmoles per liter. It is proposed that continuous intravenous glycerol be considered for treatment of cerebral edema in patients not able to take oral glycerol.

Enhancement of alimentary hyperglyceridemia by fructose and glycerol in man.

SummarySingle oral doses of fructose and glycerol administered to normoglycerldeniK-human subjects after a standard fat meal increase the postprandial hvpergiyceridemhi while glucose given in a similar way decreases the serum triglyceride response. It is tentatively suggested that the effect of fructose and glycerol is due to a stimulation of intestinal synthesis of triglycerides from endogenous fatty acids. The opposite effect of glucose might be attributed to an accelerated elimination of triglycerides from the blind possibly mediated by insulin.

Fate of intravenously administered glycerol.

SummaryIntravenously administered glycerol rapidly disappears from the bloodstream. Single injections of 6 g glycerol did not produce excessive urinary excretion of glycerol but 12 g led to excretion of one-third the dose. Daily infusions of large doses of glycerol produced marked polyuria and in some animals led to tremors and convulsions. These disturbances were not caused by accumulation of glycerol in the blood.

Glycerol Toxicity and Hemoglobinuria in Relation to Vitamin G

SummaryThe administration of ascorbic acid prior to a parenteral dose of glycerol will raise the dose necessary to produce hemoglobinuria by 100% or more. The ascorbic acid may be effective in lowering the mortality rate from toxic doses of parenteral glycerol.The authors wish to express their appreciation for the helpful suggestions of Dr, E. M. K. Geiling.